MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Ling Tao; Mahmoud A. Mohammad; Giorgio Milazzo; Myrthala Moreno-Smith; Tajhal D. Patel; Barry Zorman; Andrew Badachhape; Blanca E. Hernandez; Amber B. Wolf; Zihua Zeng; Jennifer H. Foster; Sara Aloisi; Pavel Sumazin; Youli Zu; John Hicks; Ketan B. Ghaghada; Nagireddy Putluri; Giovanni Perini; Cristian Coarfa; Eveline Barbieri

doi:10.1038/s41467-022-31331-2

MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Ling Tao, Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H. Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, Eveline Barbieri

Research output: Contribution to journal › Article › peer-review

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Abstract

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

Original language	English (US)
Article number	3728
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31331-2
State	Published - Dec 2022

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-31331-2

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Tao, L., Mohammad, M. A., Milazzo, G., Moreno-Smith, M., Patel, T. D., Zorman, B., Badachhape, A., Hernandez, B. E., Wolf, A. B., Zeng, Z., Foster, J. H., Aloisi, S., Sumazin, P., Zu, Y., Hicks, J., Ghaghada, K. B., Putluri, N., Perini, G., Coarfa, C., & Barbieri, E. (2022). MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma. Nature Communications, 13(1), [3728]. https://doi.org/10.1038/s41467-022-31331-2

Tao, L, Mohammad, MA, Milazzo, G, Moreno-Smith, M, Patel, TD, Zorman, B, Badachhape, A, Hernandez, BE, Wolf, AB, Zeng, Z, Foster, JH, Aloisi, S, Sumazin, P, Zu, Y, Hicks, J, Ghaghada, KB, Putluri, N, Perini, G, Coarfa, C & Barbieri, E 2022, 'MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma', Nature Communications, vol. 13, no. 1, 3728. https://doi.org/10.1038/s41467-022-31331-2

@article{0a268574b67144a0bf9b64368a22a1b4,

title = "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma",

abstract = "Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.",

author = "Ling Tao and Mohammad, {Mahmoud A.} and Giorgio Milazzo and Myrthala Moreno-Smith and Patel, {Tajhal D.} and Barry Zorman and Andrew Badachhape and Hernandez, {Blanca E.} and Wolf, {Amber B.} and Zihua Zeng and Foster, {Jennifer H.} and Sara Aloisi and Pavel Sumazin and Youli Zu and John Hicks and Ghaghada, {Ketan B.} and Nagireddy Putluri and Giovanni Perini and Cristian Coarfa and Eveline Barbieri",

note = "Funding Information: We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick{\textquoteright}s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children{\textquoteright}s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center. {\texttrademark} Funding Information: We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER{\texttrademark}cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick{\textquoteright}s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children{\textquoteright}s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-31331-2",

language = "English (US)",

volume = "13",

journal = "Nat Commun",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

AU - Tao, Ling

AU - Mohammad, Mahmoud A.

AU - Milazzo, Giorgio

AU - Moreno-Smith, Myrthala

AU - Patel, Tajhal D.

AU - Zorman, Barry

AU - Badachhape, Andrew

AU - Hernandez, Blanca E.

AU - Wolf, Amber B.

AU - Zeng, Zihua

AU - Foster, Jennifer H.

AU - Aloisi, Sara

AU - Sumazin, Pavel

AU - Zu, Youli

AU - Hicks, John

AU - Ghaghada, Ketan B.

AU - Putluri, Nagireddy

AU - Perini, Giovanni

AU - Coarfa, Cristian

AU - Barbieri, Eveline

N1 - Funding Information: We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick’s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children’s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center. ™ Funding Information: We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER™cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick’s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children’s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

AB - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

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JO - Nat Commun

JF - Nat Commun

SN - 2041-1723

IS - 1

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ER -

MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

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